research article brain-gut axis modulation of acupuncture in...

Research ArticleBrain-Gut Axis Modulation of Acupuncture in FunctionalDyspepsia: A Preliminary Resting-State fcMRI Study

Jiliang Fang,1 Danhong Wang,2 Qing Zhao,1 Yang Hong,1 Yulian Jin,3

Zhishun Liu,3 Kehua Zhou,4 Xianghong Jing,5 Xiaochun Yu,5 Ruiqi Pan,2

Andrew Chang,6 Hesheng Liu,2 and Bing Zhu5

1Department of Radiology, Guang An Men Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China2Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA3Department of Acupuncture and Moxibustion, Guang An Men Hospital, China Academy of Chinese Medical Sciences,Beijing 100053, China4Department of Health Care Studies, Daemen College, Amherst, NY 14226, USA5Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China6Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA

Correspondence should be addressed to Hesheng Liu; [email protected] Bing Zhu; [email protected]

Received 22 July 2015; Accepted 20 September 2015

Academic Editor: Morry Silberstein

Copyright © 2015 Jiliang Fang et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Objective. To explore acupuncture effects on brain functional connectivity in patients with functional dyspepsia (FD). Methods.Eight patients in an acupuncture treatment group and ten healthy adults in the control group participated in the study. Acupunctureeffectivenesswas evaluated based on changes of the gastrointestinal symptoms, gastricmotilitymeasurements, and gastrin levels andcomparisons with the control group when appropriate. To investigate functional connectivity changes related to FD and potentialmodulation after acupuncture, a set of regions of interest (ROIs) were selected according to previous fMRI reports of acupuncture.Results. Patients showed significant improvements of FD signs and symptoms after acupuncture treatments. For all of the ROIs,we identified subportions of the networks showing reduced connectivity in patients with FD. Connectivity between the ROIs andcorresponding disease targets showed significant improvement after acupuncture treatment (𝑃 < 0.05) in all ROIs except for rightmedial temporal lobe-hippocampus and right inferior parietal lobule. Conclusion. Functional connectivity of the brain is changedin patients with FD but approximates that in healthy control after acupuncture treatment. The relief of gastrointestinal signs andsymptoms by acupuncture is likely due to the normalization of brain-gut axis associated with FD.

1. Introduction

Functional dyspepsia (FD) is a common gastrointestinaldisorderwithout evidence of an organic gastric disease, whichaffects around 11% to 29.2% of the general population [1].Despite its high prevalence, characterization of signs andsymptoms related to FD has historically been vague and evenflawed [2].Themost current definition of FD, as per the RomeIII consensus, identifies four characteristic FD symptoms,all assumed to stem from the gastroduodenal region: earlysatiation, postprandial fullness, epigastric pain, and epigastricburning [3].

In many patients, little can be determined regardingthe direct cause of FD besides the general belief that thepathophysiology of FD involves gastrointestinal dysfunction[2]. Recent studies have revealed that the disturbance of thebrain-gut axis may be involved in the development of FD[4]. The brain-gut axis refers to a complex, bidirectionalcommunication system between the gastrointestinal tractand the nervous system [5]. The brain-gut axis not onlyensures gastrointestinal homeostasis and digestion but alsois closely related to affect, motivation, and higher cognitivefunctions, including intuitive decision [4]. As the importanceof the human brain in FD becomes more widely recognized,

Hindawi Publishing CorporationEvidence-Based Complementary and Alternative MedicineVolume 2015, Article ID 860463, 11 pageshttp://dx.doi.org/10.1155/2015/860463

2 Evidence-Based Complementary and Alternative Medicine

the evolving treatments of FD began to include drugs target-ing at the human brain in addition to typical drugs directlymodulating gastrointestinal function [3].

Despite the availability of pharmaceutical interventions,treatments of FD remain unsatisfactory [3]. During the pastdecades, acupuncture has gained popularity in the manage-ment of FD in both China and other Eastern Asian countries.The effectiveness of acupuncture treatment for FD has beensupported by some previous studies [6]. For example, Parket al. [7] reported that acupuncture could improve dyspepticsymptoms and quality of life in patients with FD; Ma et al.[8] echoed these results and found acupuncture inducedsignificant symptom relief in as high as 70.69% of patientswith FD.

Outside of studies strictly on the therapeutic effective-ness of acupuncture on FD, interest in the general effectsof acupuncture stimulation on brain activities of patientswith FD has also been explored. Using positron emis-sion tomography-computed tomography (PET-CT) scan-ning, Zeng et al. [9] identified differences in glycometabolismin certain brain regions of patients with FD as compared tohealthy controls and concluded that theAFC (anterior frontalcortex), PCC (posterior cingulate cortex), and caudate tailare areas potentially involved in FD. Acupuncture treatmentdecreased glycometabolism in the postcentral gyrus andcerebellum and caused simultaneous deactivation of theACC (anterior cingulate cortex), insula, and hypothalamus inpatients with FD [9, 10]. These findings suggest a potentialmechanism that acupuncture treatment may improve FDsymptoms by acting on particular brain areas.

A powerful approach to analyze large-scale brain net-works and their changes after acupuncture modulation isfunctional connectivity measured by resting-state fMRI.Resting-state functional connectivity measures the sponta-neous Blood Oxygenation Level Dependent (BOLD) signalcorrelation among brain regions and can provide insightinto the normally functioning brain as well as functionalabnormalities related to brain diseases [11, 12]. Using resting-state fcMRI, here we aimed to identify specific regionsshowing connectivity changes in patients with FD and furtherexplore whether the connectivity in these brain regions couldbe normalized after acupuncture treatment.

2. Methods

2.1. Participants. This is a concomitant study of a clinicaltrial which included 60 patients with FD, among whom 30were treated with acupuncture and 30 were treated with sham(nonclassic acupoint) acupuncture [13]. The study was per-formed at the Department of Acupuncture and the Depart-ment of Radiology at Guang An Men Hospital, one of thelargest teaching hospitals for traditional Chinese medicine inChina. Participants were recruited through advertisements inlocal newspapers, in posters, and on hospital website.Writteninformed consent was obtained from each subject beforestudy participation. The study protocol was approved by theEthics Committee of Guang An Men Hospital.

As part of the original clinical trial study protocol, eightout of the 30 patients in the acupuncture treatment group

were randomly selected to participate in the functional MRIstudy (2 males; mean age 48.38 ± 8.25 yrs). Ten healthyadults were recruited as a control group with age matchedto the patient group (3 males; mean age 48.80 ± 8.59 yrs).No significant age or gender difference was found betweenthese two groups (𝑃 > 0.05). Patients included in thetreatment group all met the Rome III diagnostic criteria forFD [14]. Additionally, the following inclusion criteria wereapplied for both groups: no mental disorders; age between18 and 70; no pregnancy. All medication related to thegastrointestinal system was stopped one week prior to andduring participation, whichmay include but not be limited togastric suppression drugs, prokinetics, H. pylori eradicationagents, and antidepressants.

2.2. Acupuncture Protocol. In the patient group, two mainacupoints, Zu Sanli (ST36) and Tai Xi (KI3), were used;additional acupoints included Zu Linqi (GB 41), Nei Guan(PC 6), and Shen Men (HT 7). Rationales for the acupointselection were detailed in a previous publication [13]. Classicacupoints were localized according to the 2008World HealthOrganization standards [15]. Needle insertion was perpen-dicular with a depth of about 25mm. In order to reach anoptimal acupuncture sensation response which is definedas Deqi sensation including soreness, heaviness, fullness,propagation of needling sensation, and/or adjacent muscletwitching [16],moderate acupuncturemanipulation of lifting,thrusting, and twirlingwith a frequency of 120 times/minwasperformed. Prior to needle removal, the same acupuncturemanipulation technique was performed continually to reachone to three times of Deqi sensation (with short intervalbetween Deqi sensations if there was more than one Deqisensation during the first two minutes); then, the needlewas removed. If no Deqi sensation was obtained duringthe first two minutes, acupuncture needle was left in placefor 20 minutes, and one acupuncture manipulation wasagain applied right before needle removal. Treatment wasimplemented once every other day, three to four times a weekfor one month. All acupuncture procedures were performedby the same acupuncturist who had more than six yearsof clinical experiences with the Huatuo needles (diameter:0.30mm, length: 40mm; Suzhou Medical Appliance Manu-factory, Jiangsu, China).

2.3. Imaging Data Acquisition and Processing. Brain imagingwas performed on a 1.5 Tesla GE Signa MRI system equippedwith the standard two channels’ birdcage head coil. A spongycushion was used to minimize the in-scanner head motion.Functional MR images were acquired with the gradient echoEPI sequence (TE 30ms, TR 2500ms, matrix 64 × 64, FOV240mm, flip angle 90∘, slice thickness 3.5mm, and gap0.5mm, 41 slices, paralleled by AC-PC line). Six-minute-longfMRI data were acquired in the ten healthy adults as well asin each patient before and after the one-month acupuncturetreatment.

Resting-state fMRI data were processed using the follow-ing steps that have been used in previous published studies:(1) slice timing correction (SPM2, Wellcome Department

Evidence-Based Complementary and Alternative Medicine 3

of Cognitive Neurology, London, UK); (2) rigid body cor-rection for head motion with the FSL package [17, 18]; (3)normalization for global mean signal intensity across runs;and (4) low-pass temporal filtering (0.01Hz–0.08Hz), headmotion regression, and ventricular and white matter signalregression. Whole brain signal regression was also includedin the processing stream, which can improve the correctionof motion related artifacts [19, 20]. Data of two healthy adultswere discarded after quality control due to excessive headmotion. All subjects included in the final analyses had metthe quality control criterion of slice-based temporal signal-to-noise ratio >100 [21]. The resting-state data were analyzedusing region-based correlation analysis, often referred to asfunctional connectivity MRI (fcMRI) analysis. The presentmethods extend from Biswal et al. [22] and are described indetail by Wang et al. [23].

To investigate functional connectivity changes relatedto FD and potential modulation after acupuncture, weselected the following regions of interest (ROIs) accordingto previous fMRI reports of acupuncture effects on thelimbic-paralimbic-neocortical network [24, 25]. These ROIsincluded pregenual ACC, sub-ACC,MTL-hippocampus, IPL,and anterior insula. Seed regionswere defined as spheres with8mm radius.

2.4. Outcome Assessment. Acupuncture effectiveness on FDwas evaluated based on subjective and objective outcomes[13]. In brief, subjective outcomes included dyspeptic symp-toms, quality of life, and mental status; objective outcomesincluded fasting serum gastrin concentration, height of gas-tric fluid retention, and frequency and propagation velocityof gastric slow wave measured by the barium swallow test.Subjective outcomes were measured in patients with FDbefore and after one month of acupuncture treatment; objec-tive outcomes were measured in healthy adults as well as inpatients with FD before and after one month of acupuncturetreatment.

The Chinese version Nepean Dyspepsia Index (NDI)was used to measure both dyspeptic symptom scores andimpairment of the dyspepsia-specific health-relatedQOL (H-QOL). NDI is dyspepsia impact scale developed by Talleyet al. [26]. Its Chinese translation version was reported tohave high reliability and validity [27]. In the present study,we selected the four cardinal dyspeptic symptoms and theircorresponding assessment as reported in the NDI. The scorefor each symptom in the checklist of cardinal dyspeptic symp-toms was calculated by adding its corresponding frequency,severity, and level of discomfort; dyspeptic symptom sumscore (DSSS) is the sum score of the four symptoms in thechecklist. Quality of life was measured by the short-form 36(SF-36) questionnaires [28]. Mental status of patients wasevaluated via Zung Self-Rating Depression Scale (SDS) [29]and Self-Rating Anxiety Scale (SAS) [30].

A fasting venous blood sample was drawn from thebasilic vein prior to breakfast early in the morning. Aboutthree milliliters of the blood sample was sent to PekingUnion Medical College Hospital for measurement of serumgastrin levels. Meanwhile, the X-ray gastric barium mealdynamic radiography was performed. The participants were

given 120mL 80% (w/v) barium sulfate suspension meal(Qingdao Dongfeng Chemical Co. Ltd., Shandong, China).Participants were then placed in a supine position withtrunk rotated. Using the digital X-ray machine (Prestige,GE, USA), gastric mucosa was observed; then, a Chinesecoin of fifty cents was placed on top of the skin over thestomach of the participant, and gastric motions around thegastric antrum were video recorded for one minute whilethe participant was in a standing position. Frequency ofgastric slow wave was directly counted as the number ofwaves that passed through the gastric antrum in one minute.Propagation velocity of gastric slow wave was assessed bythe time interval between two consecutive waves that passedthrough the gastric antrum. Heights of gastric fluid retentionweremeasured in captured pictures and calculated into actualvalues.

2.5. Statistical Analysis for FD Symptoms, Gastrin, and GastricMotility. The statistical analyses were performed by twoindependent statisticians who were blind to the treatmentsand study protocol. Statistical Analysis System (SAS), version6.12, was used and a significance level was set at 𝛼 < 0.05.

Wilcoxon signed-rank test was used to explore differencesin subjective scores and objective measurements before andafter acupuncture treatment in patients with FD. Wilcoxonrank-sum test was used to compare objective measurementsin patients with FD and healthy volunteers. All quantitativedata including subjective scores were expressed with mean ±SD.

3. Results

3.1. Subjective Outcomes. After one-month acupuncturetreatment, patients with FD showed significant improve-ments in each individual symptom score, dyspeptic symptomsum score, and SDS and SAS scores (see Table 1). Theimprovement rates vary from 29% to 100% (𝑃 < 0.05 forall comparisons); the quality of life in patients with FD wassignificantly improved with a 40% increase in SF-36 scores(Table 1).

3.2. Objective Outcomes. Before treatment, patients with FDdemonstrated lower levels of fasting serum gastrin concen-tration and frequency andpropagation velocity of gastric slowwave than healthy adults (𝑃 < 0.05 for all comparisons). Afterone-month acupuncture treatment, no difference in thesemeasurements was found between the patient and healthygroups (𝑃 > 0.05 for all measurements). Before acupuncturetreatment, six patients had gastric fluid retention with ameanheight of 44.35mm; after the treatment, no patient demon-strated measurable gastric fluid retention (see Table 2).

3.3. The Changes of Functional Connectivity Associated withFD. To explore potential functional connectivity changesassociated with FD and the modulation effect of acupuncturetreatment, we computed the functional connectivity mapsusing ten predefined ROIs in the default network andattentional network, including pregenual ACC, subgenual


Table 1: Subjective measurements (symptoms scores) of 8 patients with FD (mean ± SD).

Measurements 𝑁 Baseline After Difference Improvement (%) 𝑃 valuePF 8 9.75 ± 1.75 1.63 ± 2.13 8.13 ± 2.03 83.38% <0.0001ES 8 9.75 ± 2.71 0.75 ± 2.12 9.00 ± 2.83 92.31% <0.0001EP 7 6.71 ± 2.43 0.71 ± 1.25 6.00 ± 1.91 89.42% <0.0001EBS 5 6.60 ± 2.19 0.00 ± 0.00 6.60 ± 2.19 100.00% <0.0001DSSS 8 29.5 ± 7.25 3.00 ± 4.28 26.5 ± 5.76 89.83% 0.0002SF-36 8 50.77 ± 16.22 71.20 ± 14.78 20.43 ± 22.39 40.24% 0.0364SDS 8 61.88 ± 11.68 44.00 ± 8.64 17.88 ± 12.88 28.89% 0.0057SAS 8 57.88 ± 13.00 41.00 ± 6.39 16.88 ± 13.87 29.16% 0.0108PF: postprandial discomfort; ES: early satiety; EP: epigastric pain; EBS: epigastric burning sensation; DSSS: dyspeptic symptom sum score; SF-36: short-form36 questionnaire; SDS: Self-Rating Depression Scale; SAS: Self-Rating Anxiety Scale.

Table 2: Objective measurements in patients with functional dyspepsia and healthy adults.

Items A: baseline (𝑛 = 8) B: after treatment (𝑛 = 8) C: healthy adults (𝑛 = 10) 𝑃 valuesA versus B A versus C B versus C

Gastrin (pg/ml) 25.93 ± 5.90 44.4 ± 6.26 47.65 ± 20.21 0.0002 0.0081 0.6401FGSW (n/min) 2.49 ± 0.64 3.11 ± 0.14 3.11 ± 0.13 0.0078 0.0008 1.0000PVGSW (s) 24.25 ± 4.95 19.75 ± 2.05 19.41 ± 0.93 0.0180 0.0279 0.6713FGSW: frequency of gastric slow wave; PVGSW: propagation velocity of gastric slow wave.Note: propagation velocity of gastric slow wave was assessed by the time interval between two consecutive waves that passed through the gastric antrum.

ACC (sub-ACC), medial temporal lobe-hippocampus (MTL-Hippocampus), inferior parietal lobule (IPL), and anteriorinsula (Anti-Insula) in each hemisphere. Two additionalROIs were defined in the primary visual cortex for a controlanalysis (Table 3).

In each of the three groups (control and pre- and post-treatment groups), we identified the regions demonstratingstrong functional connectivity to the ROIs ((a) in Figures1–4). For each ROI, we then identified the regions showingstrong connectivity difference between the healthy controlgroup and the pretreatment group (mean group difference𝑍 > 0.1). These regions were considered as the “diseasetargets,” representing the regions whose connectivity withthe ROIs was affected by FD ((c) in Figures 1–4). We thenexamined if the connectivity between each ROI and itscorresponding “disease target” can be normalized by theacupuncture treatment. The connectivity values betweeneach ROI and its corresponding disease target were plotted((b) in Figures 1–4) and compared between the pre- andposttreatment groups.

For all of the ROIs in the default and attentional network,we could identify subportions of the networks showingreduced connectivity in patients with FD (see (c) in Figures1–4). Connectivity between the ROIs and corresponding dis-ease targets showed significant improvement after acupunc-ture treatment (𝑃 < 0.05, Wilcoxon paired nonparametrictest) in all ROIs except for rightMTL-hippocampus and rightIPL.

As a control analysis, we placed ROIs in the primaryvisual cortex because it is known that acupuncture does nothave significant effect on the visual system in FD treatment[9, 10, 31]. The goal of this control analysis is to test whetherthe posttreatment improvement was due to any data quality

Table 3: Locations of seed regions used to quantify effectiveness ofacupuncture.

Seed region MNI coordinatesLeft/right Anti-Insula −32, 24, −8/32, 24, −8Left/right pACC −3, 48, 7/3, 48, 7Left/right sub-ACC −10, 32, −6/10, 32, −6Left/right IPL −46, −68, 36/50, −62, 32Left/right MTL-hipp −26, −20, −18/26, −20, −18Left/right vision −10, −82, 8/10, 82, 8

difference between groups. We found some regions showingreduced connectivity to visual ROIs in patients with FD.However, the connectivity was not changed after acupuncturetreatment (Figure 5).

Of note, no significant correlation was found between theconnectivity changes in these brain regions with the changesof patients’ clinical symptoms, gastric motility scores, andserum gastrin concentration. This is partially due to the lim-ited number of subjects and potentially highly complicatedneural mechanisms responsible for the symptoms.

4. Discussion

4.1. Effect of Acupuncture on Functional Dyspepsia Symptomsand Signs. Thehistory of acupuncture treatment for digestiveproblems like FDdates back thousands of years; the beneficialeffects of acupuncture for FD have been noted by generationsof practitioners and are supported by modern research [6–8]. Through randomized controlled trials, previous studiesreported that patients with FD experienced improvements


Left pregenual ACC Right pregenual ACC Control Pretreatment PosttreatmentControl Pretreatment Posttreatment

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Figure 1: Functional connectivity maps of controls and pretreatment and posttreatment groups were computed based on the pregenualACC ROI (a). The left pregenual ACC seed region was connected with insula, dorsal lateral prefrontal cortex (dLPFC), medial prefrontalcortex, supramarginal gyrus, and superior andmiddle temporal gyri.The right pregenual ACC seed region was connected with insula, medialprefrontal cortex, middle cingulate gyrus, lateral prefrontal cortex, supramarginal gyrus, and middle temporal gyrus. Reduced connectivitywas found in pretreatment group compared with healthy adults. These brain regions, termed disease targets, represent the regions associatedwith the FD disease (c). After treatment, connectivity was enhanced with the tendency to approximate the healthy controls. The connectivityvalues between pregenual ACC and the disease target were plotted for controls and pretreatment and posttreatment groups (b).

in FD symptoms after classic acupuncture treatment ascompared with acupuncture at nondefined points after twoto four weeks of treatment [7, 8, 10]. In another study,Lima et al. [32] found that combining drug therapy andclassic acupuncture treatment was superior to combiningdrug therapy and acupuncture at nondefined acupoints.The alleviation of symptoms reported in the present studyis consistent with the previous studies on the effects of

acupuncture [6–8], supporting the efficacy of acupuncturetreatment in gastrointestinal disorders like FD.

In the present study, acupuncture was found to increaseserum fasting gastrin level in patients with FD toward normalvalues of healthy controls. The result was consistent withprevious acupuncture studies [33, 34]. Increased secretion ofserum fasting gastrin has been reported by Chang et al. [33]using acupuncture at ST36 andZhang [34] using acupuncture


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Figure 2: Regions connected with the sub-ACC ROI. The regions strongly correlated with left sub-ACC included dorsal lateral prefrontalcortex, supramarginal gyrus, medial prefrontal cortex, andmedial supplementary motor area.The right sub-ACC correlated regions includedmedial prefrontal cortex, middle cingulate gyrus, and frontal pole.

at simultaneous front-Shu and back-Mu acupoints. Nonethe-less, the enhanced secretion of gastrin and brain effects ofacupuncture as demonstrated in the present study suggestedthat the relief of FD symptoms by acupuncture may be due toits modulation of the brain-gut axis.

4.2. Altered Brain Functional Connectivity in the Brain-GutAxis of FD and the Acupuncture Effects. The involvement ofthe brain-gut axis in gastrointestinal system homeostasis iswidely supported with understandings of the enteric nervoussystem and the neurobiological pathways involved in itsmod-ulation. Previous studies have demonstrated the involvement

of the brain-gut axis in digestive disorders similar to FD. Forexample, an investigation of irritable bowel syndrome (IBS)using fMRI reported that psychosocial stress and activationof three brain areas (midcingulate cortex, somatosensorycortex, and prefrontal area) were associated with worsenedIBS symptoms [35]. In the same study, researchers alsofound that improvements in IBS symptoms were associatedwith decreased activation of these particular brain regions[35]. Additionally, Jonsson et al. [36] reported that anxiety-provoking interview increased gastrin levels in patients withFD. These findings suggest that emotional and psycholog-ical changes may affect functions of the digestive system.


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Figure 3: Seeds were placed in MTL-hippocampus and IPL. Treatment-related improvement only showed in the left hemisphere. The leftMTL-hippocampus seed regions were correlated with lateral prefrontal cortex, orbital gyrus, and middle and posterior cingulate gyrus. Theregions strongly correlated with left IPL seed included inferior lateral prefrontal cortex, supramarginal gyrus, posterior cingulate anteriorcingulate cortex, and medial prefrontal cortex.

One of the understandings in such a phenomenon could bedue to the close relationship between the enteric nervoussystem (ENS) and the central nervous system (CNS). In areview article, Natale et al. [37] summarized recent researchstudies and concluded that misfolded protein aggregatesin both the ENS and CNS in neurodegenerative diseasescan theoretically impact the gastrointestinal functions inpatients with neurodegenerative disorders. Our previousstudies demonstrated that acupuncture could modulate thelimbic-paralimbic-neocortical network and limbicprefrontal

regions that are essential for emotional control and cognition[24, 25]. Thus, it is possible that acupuncture modulatesspecific brain cognitive networks of the brain-gut axis inpatients with FD.

Consistent with the hypothesis, acupuncture has beenfound to affect brain activities in patients with FD [9, 10, 31].Using PET-CT, researchers identified various brain regionsrelated to possible abnormal brain activities and the modu-latory effects of acupuncture on some of these brain regions[9, 10]. The AFC, PCC, and caudate tail areas were found to


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Figure 4: A seed was placed in anterior insula. The left seed region correlated with anterior cingulate cortex, supplementary motor area,supramarginal gyrus, and superior and middle temporal gyri. The right seed correlated with medial prefrontal cortex, medial supplementarymotor area, and middle temporal gyrus.

be potentially involved in FD [9, 10]. While PET-CT may beable to detect intrinsic activities of the human brain basedon metabolic activities [9], fMRI provides another tool forthe exploration of central effects of acupuncture on FD. In afMRI study, Liu et al. [31] found positive correlations betweenthe activity in dorsomedial prefrontal cortex (dmPFC) andpregenual anterior cingulate cortex (pACC) and the symptomseverity, as well as positive correlations between the activity inmiddle cingulate cortex (MCC), OFC, insula, temporal pole(TP), and FD duration.

Using resting-state fcMRI, the present study investigatedfunctional connectivity abnormalities in FDand the potential

effect of acupuncture on connectivity. We identified a set ofbrain regions that demonstrated reduced functional connec-tivity in patients with FD, including regions in the defaultand attentional networks that are suggested to be responsiblefor symptoms related to depression and psychosis [24, 25,38]. Our results thus provide evidence for the brain-gut axistheory connecting functions of the gastrointestinal systemwith the central nervous system.

Importantly, we found that connectivity was enhancedwith the tendency to approximate the healthy controls afteracupuncture treatment. Acupuncture tended to normalizechanges of brain activities in the aforementioned brain areas,



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Figure 5: As a control analysis, two seeds were placed in the primary visual cortex. Patients with FD showed reduced connectivity betweensome sensorimotor regions and visual cortex. However, there was no improvement after acupuncture treatment.

such as connectivity between pregenual ACC andmedial pre-cuneus, bilateral frontal pole, orbital gyrus and medial gyrusof the frontal cortex (BA10, BA11), and bilateral middle gyrusof frontal cortex (BA43, BA45, and the middle lower part ofBA4) in patients with FD; these results are partially consistentwith previous research studies which demonstrated positiveeffects of acupuncture on patients with FD. Our results addfurther credence to acupuncture’s role in normalizing thebrain-gut axis related to FD.

Certainly, our sample size of eight patients in this studywas relatively small, in part due to difficulties in obtainingfcMRI scan data for a large number of patients before andafter acupuncture. Nonetheless, we believe that the subjective

and objective outcome results, as well as the imaging findings,strongly support the fact that acupuncture can effectivelytreat FD by modulating neural activity in specific cognitivebrain regions. Further investigation of functional connec-tivity and the brain’s role in the pathophysiology should bepursued with a larger number of subjects.

5. Conclusions

Functional connectivity of the brain is changed in patientswith FD but approximates that in healthy control afteracupuncture treatment. The relief of gastrointestinalsigns and symptoms in FD by acupuncture is likely due


to the normalization of brain-gut axis associated withFD.

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper.

Authors’ Contribution

J. Fang, B. Zhu, Z. Liu, and H. Liu contributed to studyconcept and design. Y. Jin, Q. Zhao, and Y. Hong contributedto recruitment, enrollment, and assessment of patients. Q.Zhao, Y. Hong, and Y. Jin contributed to acquisition of data.J. Fang, H. Liu, D. Wang, A. Chang, and R. Pan contributedto analysis and interpretation of data. B. Zhu, H. Liu, J. Fang,X. Yu, and X. Jing contributed to study supervision. J. Fang,D. Wang, K. Zhou, and H. Liu contributed to drafting of thepaper. All authors approved the final version of the paper.Jiliang Fang and Danhong Wang contributed equally.

Acknowledgments

This study was funded by the State Key Development Pro-gram for Basic Research of China (973, Grant 2011CB505202)and theNationalNatural Science Foundation ofChina (Grant30870668 and Grant 81273674).

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